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Parkinson disease (PD) is a heterogeneous and progressive neurodegenerative disorder. PD was traditionally defined as a movement disorder resulting from loss of dopamine in the basal ganglia, but its pathology is now known to be more widespread, involving both the central and peripheral nervous system, and leading to various motor and nonmotor signs and symptoms. Recent discoveries have led to major insights into the neurobiology of PD, in particular the pathophysiology and the central role of cellular α-synuclein aggregation in the pathogenesis of genetic and sporadic forms of PD. While insights into the pathophysiology have resulted in novel pharmacological and surgical therapies addressing the parkinsonian motor signs, efforts to halt the progression of the disease have so far failed. Exploration of novel molecular and interventional targets in genetic cellular and animal models and the introduction of biomarkers to stratify patients for clinical trials offer hope for the development of more effective symptomatic and neuroprotective therapies.

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson’s Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation.

In the primate thalamus, the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM) receive GABAergic projections from the internal globus pallidus (GPi) and glutamatergic inputs from motor cortices. In this study, we used electron microscopy to assess potential structural changes in GABAergic and glutamatergic microcircuits in the VApc and CM of MPTP-treated parkinsonian monkeys. The intensity of immunostaining for GABAergic markers in VApc and CM did not differ between control and parkinsonian monkeys. In the electron microscope, three major types of terminals were identified in both nuclei: (a) vesicular glutamate transporter 1 (vGluT1)-positive terminals forming asymmetric synapses (type As), which originate from the cerebral cortex, (b) GABAergic terminals forming single symmetric synapses (type S1), which likely arise from the reticular nucleus and GABAergic interneurons, and (c) GABAergic terminals forming multiple symmetric synapses (type S2), which originate from GPi. The density of As terminals outnumbered that of S1 and S2 terminals in VApc and CM of control and parkinsonian animals. No significant change was found in the abundance and synaptic connectivity of S1 and S2 terminals in VApc or CM of MPTP-treated monkeys, while the prevalence of "As" terminals in VApc of parkinsonian monkeys was 51.4% lower than in controls. The cross-sectional area of vGluT1-positive boutons in both VApc and CM of parkinsonian monkeys was significantly larger than in controls, but their pattern of innervation of thalamic cells was not altered. Our findings suggest that the corticothalamic system undergoes significant synaptic remodeling in the parkinsonian state.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson’s disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward., SCOPUS: re.j, info:eu-repo/semantics/published

The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates. We report an extensive pharmacokinetic study using subcutaneous (SC) administration of CNO in five adult rhesus monkeys. CNO reached maximal plasma and cerebrospinal fluid (CSF) concentrations within 2 h after injection, with an observed dose-dependent increase in levels following a 3 and 10 mg/kg SC dose. Since CSF concentrations were below values predicted from unbound plasma concentrations, we investigated whether CNO was restricted from the CNS through active transport at the blood-brain barrier. In vitro assessment demonstrated that CNO is a substrate for P-glycoprotein (Pgp; efflux ratio, 20), thus providing a likely mechanism limiting CNO levels in the CNS. Furthermore, CNO is metabolized to the psychoactive compounds clozapine and n-desmethylclozapine in monkeys. The concentrations of clozapine detected in the CSF are sufficient to activate several types of receptor (including the hM-DREADDs). Our results suggest that CNO metabolism and distribution may interfere with reproducibility and interpretation of DREADD-related experiments in NHPs and calls for a re-evaluation of the use of CNO in DREADD-related experiments in NHPs along with the need to test alternative compounds.

Parkinsonism is associated with changes in oscillatory activity patterns and increased synchronization of neurons in the basal ganglia and cortex in patients and animal models of Parkinson's disease, but the relationship between these changes and the severity of parkinsonian signs remains unclear. We examined this relationship by studying changes in local field potentials (LFPs) in the internal pallidal segment (GPi) and the subthalamic nucleus (STN), and in encephalographic signals (EEG) from the primary motor cortex (M1) in Rhesus monkeys which were rendered progressively parkinsonian by repeated systemic injections of small doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Observations during wakefulness and sleep (defined by EEG and video records) were analyzed separately. The severity of parkinsonism correlated with increases in spectral power at frequencies below 15.5 Hz in M1 and GPi and reductions in spectral power at frequencies above 15.6 Hz with little change in STN. The severity of parkinsonism also correlated with increases in the coherence between M1 EEG and basal ganglia LFPs in the low frequency band. Levodopa treatment reduced low-frequency activity and increased high-frequency activity in all three areas, but did not affect coherence. The state of arousal also affected LFP and EEG signals in all three structures, particularly in the STN. These results suggest that parkinsonism-associated changes in alpha and low-beta band oscillatory activity can be detected early in the parkinsonian state in M1 and GPi. Interestingly, oscillations detectable in STN LFP signals (including oscillations in the beta-band) do not appear to correlate strongly with the severity of mild-to-moderate parkinsonism in these animals. Levodopa-induced changes in oscillatory M1 EEG and basal ganglia LFP patterns do not necessarily represent a normalization of abnormalities caused by dopamine depletion.

T-type calcium channels (Cav3) are key mediators of thalamic bursting activity, but also regulate single cells excitability, dendritic integration, synaptic strength and transmitter release. These functions are strongly influenced by the subcellular and subsynaptic localization of Cav3 channels along the somatodendritic domain of thalamic cells. In Parkinson’s disease, T-type calcium channels dysfunction in the basal ganglia-receiving thalamic nuclei likely contributes to pathological thalamic bursting activity. In this study, we analyzed the cellular, subcellular, and subsynaptic localization of the Cav3.1 channel in the ventral anterior (VA) and centromedian/parafascicular (CM/Pf) thalamic nuclei, the main thalamic targets of basal ganglia output, in normal and parkinsonian monkeys. All thalamic nuclei displayed strong Cav3.1 neuropil immunoreactivity, although the intensity of immunolabeling in CM/Pf was significantly lower than in VA. Ultrastructurally, 70–80 % of the Cav3.1-immunoreactive structures were dendritic shafts. Using immunogold labeling, Cav3.1 was commonly found perisynaptic to asymmetric and symmetric axo-dendritic synapses, suggesting a role of Cav3.1 in regulating excitatory and inhibitory neurotransmission. Significant labeling was also found at non-synaptic sites along the plasma membrane of thalamic neurons. There was no difference in the overall pattern and intensity of immunostaining between normal and parkinsonian monkeys, suggesting that the increased rebound bursting in the parkinsonian state is not driven by changes in Cav3.1 expression. Thus, T-type calcium channels are located to subserve neuronal bursting, but also regulate glutamatergic and non-glutamatergic transmission along the whole somatodendritic domain of basal ganglia-receiving neurons of the primate thalamus.

Deep brain stimulation (DBS) is highly effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson’s disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal ganglia-thalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

The striatum and the subthalamic nucleus are the main entry points for cortical information to the basal ganglia. Parkinson’s disease affects not only the function, but also the morphological integrity of some of these inputs and their synaptic targets in the basal ganglia. Significant morphological changes in the cortico-striatal system have already been recognized in patients with Parkinson’s disease and in animal models of the disease. To find out whether the primate cortico-subthalamic system is also subject to functionally relevant morphological alterations in parkinsonism, we used a combination of light and electron microscopy anatomical approaches and in vivo electrophysiological methods in monkeys rendered parkinsonian following chronic exposure to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the light microscopic level, the density of vesicular glutamate transporter 1-positive (i.e. cortico-subthalamic) profiles in the dorsolateral part of the subthalamic nucleus (i.e. its sensorimotor territory) was 26.1% lower in MPTP-treated parkinsonian monkeys than in controls. These results were confirmed by electron microscopy studies showing that the number of vesicular glutamate transporter 1-positive terminals and of axon terminals forming asymmetric synapses in the dorsolateral subthalamic nucleus was reduced by 55.1% and 27.9%, respectively, compared with controls. These anatomical findings were in line with in vivo electrophysiology data showing a 60% reduction in the proportion of pallidal neurons that responded to electrical stimulation of the cortico-subthalamic system in parkinsonian monkeys. These findings provide strong evidence for a partial loss of the hyperdirect cortico-subthalamic projection in MPTP-treated parkinsonian monkeys. * Abbreviations : GPe : external globus pallidus GPi : internal globus pallidus MPTP : 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine STN : subthalamic nucleus vGluT1 : vesicular glutamate transporter 1

Because of our limited knowledge of the functional role of the thalamostriatal system, this massive network is often ignored in models of the pathophysiology of brain disorders of basal ganglia origin, such as Parkinson’s disease. However, over the past decade, significant advances have led to a deeper understanding of the anatomical, electrophysiological, behavioral and pathological aspects of the thalamostriatal system. The cloning of the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) has provided powerful tools to differentiate thalamostriatal from corticostriatal glutamatergic terminals, allowing us to carry out comparative studies of the synaptology and plasticity of these two systems in normal and pathological conditions. Findings from these studies have led to the recognition of two thalamostriatal systems, based on their differential origin from the caudal intralaminar nuclear group, the centre median/parafascicular (CM/Pf) complex, or other thalamic nuclei. The recent use of optogenetic methods supports this model of the organization of the thalamostriatal systems, showing differences in functionality and glutamate receptor localization at thalamostriatal synapses from Pf and other thalamic nuclei. At the functional level, evidence largely gathered from thalamic recordings in awake monkeys strongly suggests that the thalamostriatal system from the CM/Pf is involved in regulating alertness and switching behaviors. Importantly, there is evidence that the caudal intralaminar nuclei and their axonal projections to the striatum partly degenerate in Parkinson’s disease and that CM/Pf deep brain stimulation may be therapeutically useful in several movement disorders.

The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

Our understanding of the pathophysiology of movement disorders, and associated changes in basal ganglia activities has significantly changed in the course of the last few decades. This process began with the development of detailed anatomical models of the basal ganglia, followed by studies of basal ganglia activity patterns in animal models of common movement disorders and electrophysiological recordings in movement disorder patients undergoing functional neurosurgical procedures. These investigations first resulted in an appreciation of global activity changes in the basal ganglia in parkinsonism and other disorders, and later in the detailed description of pathological basal ganglia activity patterns, specifically burst patterns and oscillatory synchronous discharge of basal ganglia neurons. In this review we critically summarize our current knowledge of the pathological discharge patterns of basal ganglia neurons in Parkinson’s disease, dystonia and dyskinesias.

Parkinson’s disease (PD) affects more than 500,000 people in the United States, with an annual incidence of 50,000 new cases per year.1 There is a sizable proportion of PD patients whose motor symptoms cannot be adequately controlled with medications. In these patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an effective neurosurgical treatment. DBS therapy involves implanting quadripolar electrodes into specific targets in the brain and connecting the electrodes to an implanted pulse generator (IPG). The procedure is generally done in 2 stages, the first involving DBS electrode implantation and, at a later stage, IPG implantation followed by IPG programming to deliver constant stimulation at a particular voltage, rate, and pulse width. DBS programming for each patient includes the selection of appropriate electrode contacts, voltage, and pulse width to maximize efficacy and minimize side effects of stimulation. The programming process requires time-consuming assessments by experienced personnel of efficacy and side effects at each of 4 brain electrode contacts, individually and in various combinations. Improperly programmed DBS devices can be a source of inadequate symptom control.2 Information that could identify in advance the optimal contacts for stimulation would expedite and increase the accuracy of the programming process. The 4 electrode contacts, numbered 0 to 3 from most caudal to most rostral, are 1.5 mm in length, spaced 0.5 mm apart, and span a total distance of 7.5 mm (Medtronic model 3389; Medtronic Corp., Minneapolis, Minnesota). As the rostrocaudal extent of the STN is 4 to 5 mm, typically no more than 2 DBS electrode contacts are located within the STN. In addition to delivering stimulation, DBS electrodes can also be used to record local field potentials (LFPs). LFPs are thought to represent aggregate activity from populations of neurons, synapses, axons, and glia surrounding the electrode tip. LFP recordings have been used to glean information about neural rhythms involving the STN and surrounding structures.3 Recent data suggest that LFPs recorded from the STN can provide important clues about target localization4,5 and disease state in patients. Normal voluntary movements appear to be preceded by a decrease in the amplitude of β-band LFP oscillations and an increase in γ-band activity in the STN and other elements of the basal ganglia–thalamocortical circuitry.6 A pathological increase in the antikinetic β-band activity, as well as a decrease in the prokinetic γ-band activity, is thought to accompany parkinsonism.7 Most studies of LFP activity recorded from the STN of PD patients have been conducted in the immediate postoperative period. In this study, we chose to record LFP activity 3 weeks after electrode implantation, when the potentially confounding effect on neuronal activity posed by the focal cerebral edema induced by surgery can be expected to have abated. Thus, 48 hours of LFP recordings were obtained at the time when patients with implanted DBS electrodes returned to the hospital for surgery to connect their previously implanted DBS electrodes to the IPG. Our goal was to test the hypothesis that LFP data recorded from DBS electrodes could be used to identify the optimal contact(s) for postoperative DBS programming. To this end, patients underwent postoperative DBS programming, and results were then compared with LFP data collected from each contact to check for correlations. In addition, we compared the results of the postoperative LFP recordings with LFP recordings made during the DBS electrode implantation procedure to examine the utility of intra-operative LFP recordings in guiding electrode contact selection for IPG programming.

Dopamine acts through the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor families. Various studies have shown a preponderance of presynaptic dopamine D1 receptors on axons and terminals in the internal globus pallidus (GPi) and substantia nigra reticulata (SNr), but little is known about D5 receptors distribution in these brain regions. In order to further characterize the potential targets whereby dopamine could mediate its effects in basal ganglia output nuclei, we undertook a comparative electron microscopic analysis of D1 and D5 receptors immunoreactivity in the GPi and SNr of rhesus monkeys. At the light microscopic level, D1 receptor labeling was confined to small punctate elements, while D5 receptor immunoreactivity was predominantly expressed in cellular and dendritic processes throughout the SNr and GPi. At the electron microscopic level, 90% of D1 receptor labeling was found in unmyelinated axons or putative GABAergic terminals in both basal ganglia output nuclei. In contrast, D5 receptor labeling showed a different pattern of distribution. Although the majority (65–75%) of D5 receptor immunoreactivity was also found in unmyelinated axons and terminals in GPi and SNr, significant D5 receptor immunolabeling was also located in dendritic and glial processes. Immunogold studies showed that about 50% of D1 receptor immunoreactivity in axons was bound to the plasma membrane providing functional sites for D1 receptor-mediated effects on transmitter release in GPi and SNr. These findings provide evidence for the existence of extrastriatal pre- and postsynaptic targets through which dopamine and drugs acting at D1-like receptors may regulate the basal ganglia outflow and possibly exert some of their anti-parkinsonian effects.

Ablative and chronic stimulation procedures targeting the internal pallidum (GPi) and the subthalamic nucleus (STN) have led to major advancements in the treatment of Parkinson's disease and other movement disorders. Although these procedures have evolved to primarily target the posterior ventrolateral sensorimotor portion of GPi and to less selectively target STN, centrally, the ideal targets within these structures remain to be fully established. In this study, we sought to identify the optimal targeting sites in GPi and STN for reversal of parkinsonian signs through a series of reversible injections of the GABA(A) agonist muscimol in these nuclei in parkinsonian primates. Akinesia and bradykinesia were strongly ameliorated by discrete inactivation within the centromedial extent of the sensorimotor territory in GPi and the lateral portion of the sensorimotor territory in STN. This suggests that akinesia and bradykinesia might, in fact, originate from abnormalities in the same, or at least overlapping, motor circuits in the parkinsonian state. Inactivation of areas outside of the motor territories did not improve parkinsonism but induced circling and behavioral abnormalities. The segregation of basal ganglia-thalamocortical circuits appears to be therefore maintained, at least to a large extent, in the parkinsonian state. These results underscore that inactivation of discrete regions in the central territory of GPi and the lateral portion of STN are sufficient to ameliorate parkinsonian motor signs and that extension of lesions into nonmotor territories may be deleterious. Surgical outcomes might therefore be optimized by placing more discrete lesions and by restricting the extent of chronic stimulation.

The temperature dependence of the diffusion coefficient of particles is studied on lattices with disorder. A model is investigated with both trap and barrier disorder that was introduced before by Limoge and Bocquet (1990 Phys. Rev. Lett. (65) 60) to explain an Arrhenian temperature-dependence of the diffusion coefficient in amorphous substances. We have used a generalized effective-medium approximation (EMA) by introducing weighted transition rates as inferred from an exact expression for the diffusion coefficient in one-dimensional disordered chains. Monte Carlo simulations were made to check the validity of the approximations. Approximate Arrhenian behavior can be achieved in finite temperature intervals in three- and higher-dimensional lattices by adjusting the relative strengths of the barrier and trap disorder. Exact Arrhenian behavior of the diffusion coefficient can only be obtained in infinite dimensions., 18 pages LaTex, 3 embedded encapsulated Postscript figures, to be published in: J. of Phys.: Condensed Matter

In the 1960s, ablative stereotactic surgery was employed for a variety of movement disorders and psychiatric conditions. Although largely abandoned in the 1970s because of highly effective drugs, such as levodopa for Parkinson's disease (PD), and a reaction against psychosurgery, the field has undergone a virtual renaissance, guided by a better understanding of brain circuitry and the circuit abnormalities underlying movement disorders such as PD and neuropsychiatric conditions, such as obsessive compulsive disorder. High-frequency electrical deep brain stimulation (DBS) of specific targets, introduced in the early 1990s for tremor, has gained widespread acceptance because of its less invasive, reversible, and adjustable features and is now utilized for an increasing number of brain disorders. This review summarizes the rationale behind DBS and the use of this technique for a variety of movement disorders and neuropsychiatric diseases.